Biosimilar Immunogenicity, Antibodies, and Extrapolation

Based on the clinical studies to date, most clinicians and policy makers would be surprised if a biosimilar did not yield the same patient efficacy outcomes as the originator biologic. We’ve become accustomed to seeing these equivalent results. However, one of the greatest concerns of physicians and patients in biosimilar development has been the potential safety of the biosimilar when it replaces an originator product.

This concern is largely driven by the type of immunogenetic response the biosimilar molecule might elicit. What is the likelihood that it will result in the production of neutralizing antibodies, which would affect the clinical effectiveness of the product? The appearance of antidrug antibodies could theoretically cause serious immunogenic reactions, beyond just injection-site reactions, including anaphylaxis. Years of experience gained in the US and Europe with the first generation of approved biosimilars (filgrastim, epoetin, etc) have demonstrated that these concerns are unfounded. The question is just beginning to be addressed for the first biosimilar monoclonal antibodies approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Clinical studies of patients who received Inflectra®, Amjevita®, or Erelzi® showed that immunogenicity was not significantly different between these and the originator products. However, their use for other approved autoimmune disorders (i.e., extrapolation) seem to concern those clinicians expressing discomfort with biosimilar prescribing. Usually, studies of the biosimilar do not address ankylosing spondylitis if the principal clinical studies involved rheumatoid arthritis. This is why the FDA weighs so heavily the importance of analyzing the equivalence of a compound’s structure and characterization. Even these characterizations do not necessarily predict the risk of immunogenicity in practice.

According to the FDA, a head-to-head study in treatment-naïve patients is the most sensitive way to detect potential immunogenicity differences. The FDA believes, however, that a single crossover design, in a subgroup of patients, from originator to biosimilar agent, should help quantify the immunogenicity risk. Critical measurements include the formation of antibodies (measurement of their concentrations or titers), how quickly they develop and how long they persist, and their implications for pharmacokinetics and clinical sequelae. Additionally, researchers should monitor for the neutralization by antibodies of the drug’s activity.

An interesting question that could be raised is whether the immunogenicity of the product varies in patients with different autoimmune disorders (e.g., Crohn’s disease vs. rheumatoid arthritis). Although this has not been extensively studied, the use to date of Inflectra®, for instance, in its various indications, has not revealed a significant problem.

The key is that biosimilars in clinical trials and in experience have not elicited immunogenicity responses that are significantly or clinically different than those of the originator. Comprehensive efforts at tracking and surveillance postmarketing will either put these concerns to rest or raise red flags, rather quickly.